Purity Stability & Homogeneity

Question 1

What are the three phases of pharmaceutical product quality?

Answer 1

• 1st Phase: Quality by Appearance
• 2nd Phase: Quality by Testing
• 3rd Phase: Quality by design

Question 2

Name some limitations of Conventional Product Testing

Answer 2

1. Test only a “representative” sample
2. Can only test if you know the analyte and you have a test method to do so (i.e. can only test for specific impurities)
3. You can test only if test method is validated (Specific, accurate, reliable)

Question 3

Main difference between 3rd phase and 2nd phase of Quality assurance?

Answer 3

In 3rd phase, the Quality assurance of product moved upstream (E.g. control starting materials and the processes)

Question 4

Name some Disadvantages and limitations of sterility testing?

Answer 4

1. High statistical probability of passing sterility test even when contamination level is high
2. Expensive
3. Requires time (2 weeks) to culture microorganisms (Bacteria/fungi)
4. Sterilised product cannot be released in real time (e.g. take up storage space in warehouse as deadweight)

Question 5

To overcome the limitations of sterility testing, how are sterilised products validated?

Answer 5

Based on Critical Process Parameters in the process of sterilisation, such as:

1. Temperature
2. Pressure
3. Sterilisation Time/Cycle
4. Bioburden of starting materials

Question 6

Annex 20: Quality Risk Management (QRM) comprises of?

Answer 6

1. Risk Identification
2. Risk Analysis
3. Risk Reduction
4. Risk Communication

Question 7

Name some soft skills required of a regulator/inspector, and why are they important

Answer 7

1. Confidence
2. Assertiveness
3. Integrity and impartiality
4. Perseverance (Probing Nature)
5. Tact & Diplomacy
6. Oral Communication & Negotiation Skills
7. Report WRiting &Written Communication Skills
8. Willing to travel Overseas

Question 8

The 3 definitions of Quality according to the International Organisation for Standardisation (ISO)?

Answer 8

1. Fit for Purpose (for any product)
2. Fit for Medicinal Purpose (for a medicinal product)
3. Fit for using to treat patients

Question 9

What does the Quality of a Medicinal Product includes?

Answer 9

1. Identity (of starting materials)
2. Potency (of starting materials especially API)
3. Purity (absence of undesirable matters)
4. Pharmaceutical Quality Attributes a.k.a Critical Quality Attributes (CQA) (E.g. viscosity, sterility)

Question 10

What is a contaminated medicinal product?

Answer 10

Product that contains Undesirable Foreign matters (aka comtaminants), which can be chemical or microbiological.

It may be present in any materials used, and can be introduced at any processes involved to make the product

Question 11

State the 2 classification of contaminants, and give some examples for each

Answer 11

1. Intrinsic contaminant (present inherently) , referred to as impurities, and are often SPECIFIC (e.g. excipients like water)
2. Extrinsic contaminants: Anything else that is not intrinsic, and is NON-SPECIFIC (e.g. dust from premises, saliva of production personnel)

Question 12

Why do we control impurities?

Answer 12

Overall therapeutic effect is also affected by toxicity of impurities present (on top of the pharmacological properties of API)

Question 13

Name the 5 types of intrinsic impurities that may be present in medicinal products?

Answer 13

1. Process-related impurities
2. Drug-related impurities
3. Polymorphs
4. Stereo-isomers
5. Impurities from Container-Closure system & labels

Question 14

Name a few examples and their sources of process-related impurities in API

Answer 14

• Heavy metals from reactor vessels
• Un-reacted API from starting materials
• Residual Solvents
• By-products from chemical reaction
• Residual Reagents and Catalysts from reaction

Question 15

What are drug-related impurities in API?

Answer 15

Degradation Products (after API has been formed)

Question 16

Name some examples of impurities from Primary Containers

Answer 16

1. From primary containers: e.g. polyethylene, Polyvinyl chloride
2. Plasticisers, antioxidants, lubricants (E.g. plastic cap)
3. Coating materials (Resinous and polymeric)

Question 17

How can medicinal product labels act as impurities?

Answer 17

1. Adhesive (adhere to product itself)
2. Printing ink

• Both may seep through containers and contaminate products

Question 18

How are Intrinsic contaminants controlled?

Answer 18

1. QC testing of materials and finished product by manufacturers
2. Impurity Profile by HSA Product Reviewers
3. GMP Compliance by Manufacturers
4. Periodic GMP Audits by HSA Inspectors

Question 19

What is the best way to control EXTRINSIC contaminants?

Answer 19

1. Manufacturer’s Comply to GMP
2. Periodic Audits by GMP inspectors to Verify the Compliance

(difficult to control via QC testing due to UNKNOWN contaminants)

Question 20

Name some sources of extrinsic contaminants, and name some examples of contaminants from each source

Answer 20

1. Personnel: Micro-organisms, hair, saliva
2. Equipment: Rust, lubricants, leached chemicals, product residues
3. Premises: Pests, rodents, insects, cross-contaminants with adjacent Premises, pollutants and extraneous matter

Question 21

How do we control each source of extrinsic contaminants?

Answer 21

1. Personnel: PPE, personal hygiene
2. Premises: Controlled environment, partitioned to prevent cross-contamination (such as positive air pressurisation)
3. Equipment: Materials of equipment like using clean stainless steel sampling rod to collect samples

Question 22

The rule of thumb for general assessment of contamination risk

Answer 22

Increased operations within a given facility/piece of equipment = increased risks for contamination

Question 23

Manufacturers of what kind of drugs pose the highest risk for extrinsic contamination?

Answer 23

Generic Drug manufacturers (due to non-dedicated facilities, and multiple products, which may cross-contaminate)

Question 24

The 2 main factors that can influence stability of a medicinal product?

Answer 24

1. Product-related factors

2. Environmental factors

Question 25

Name some examples, or some ways in which product-related factors can affect the stability of a medicinal product?

Answer 25

- Formulation of the product - Physio-chemical properties of drug substances - Type of container and packaging materials These can interact with the API, hence affecting its stability

Question 26

Name some environmental factors that can affect the stability of a medicinal product?

Answer 26

1. Temperature 2. Moisture 3. Light 4. Oxygen 5. Physical Stress during transportation 6. In-use Contamination during Consumption (E.g. enzymes from saliva)

Question 27

The three types of studies required to test product stability?

Answer 27

1. Real time studies (minimally 6 months under appropriate storage conditions) (E.g. Singapore --> Store at 30ºC 2. Accelerated studies: subject the product to elevated/stressed condition, such as increasing storage temperature 3. Continual stability studies

Question 28

Reasons for proper storage, distribution and handling of: 1. Any medicinal product 2. Liquid dosage forms 3. Tablets

Answer 28

1. Loss of efficacy due to product degradation 2. Loss of vehicle (e.g. by evaporation), which can increase API concentration, making doses toxic 3. Tablet hardening due to loss of moisture, which changes drug's physiochemical properties, hence changes in PK

Question 29

Briefly describe how elevated moisture or relative humidity can contribute to instability?

Answer 29

1. Formation of toxic degradation products mainly through hydrolysis (E.g. acetic acid from aspirin) 2. Loss of package integrity and label clarity = loss of critical essential info 3. Transdermal patches: Loss of adhesion. Patch may drop off = no medication administered

Question 30

Briefly describe how increased agitation and vibration during transportation can contribute to instability?

Answer 30

Ingress of micro-organisms into product due to hair-line cracks, poor container-closure etc. which may make product unsafe (especially sterile products)

Question 31

Briefly describe how poor handling of product during use can contribute to instability?

Answer 31

Contamination of product, such as eye-drop, causes drop in micro-biological quality of product, making it unsafe

Question 32

How is product homogeneity demonstrated?

Answer 32

Process Validation

Question 33

What is Process Validation?

Answer 33

Ensuring and providing documentary evidence that manufacturing processes are capable of CONSISTENTLY producing a finished product of required quality (usually consecutive three batches of product)

Question 34

List the Major steps involved in Process Validation

Answer 34

1. Establish quality specifications 2. Identify critical processes 3. Design Sampling Plan 4. Design Testing Plan 5. Set Acceptance Criteria 6. Perform Statistical Analysis

Question 35

What are some examples of tablet quality specifications?

Answer 35

Blend homogeneity, hardness, thickeness, friability, particle size, dissolution profile

Question 36

What are some Critical processes and their respective sampling plan?

Answer 36

1. Blending: 10 samples taken from top, mid and bottom of blender 2. Milling: 1 representative sample drawn from mill (≈100g) 3. Compression: 6x20 tabs collected at 4 equal intervals from tablet compression machines, for each of the compression speeds (low, target, high)

Question 37

Describe the 2 types of statistical analysis

Answer 37

1. Intra-Batch analysis: consistency of all 3 validation batches, usually by blend content uniformity test results 2. Inter-batch analysis: show equivalency among the 3 validation batches AND the pilot batch (which is used for clinical trial studies), usually by dissolution

Question 38

Two types of documentation made for Process Validation Studies?

Answer 38

1. Validation Protocol (E.g. objectives, scope, personnel responsible) i.e. info about the tests 2. Validation Report, i.e. results, with recommendations and conclusions

Question 39

What is the new approach to process validation?

Answer 39

Quality by Design (QbD), which includes: - Identifying CQA - Extensive process design and qualification - Monitoring CPPs - Verification beyond 3 production batches (to ensure continuity)

Question 40

What was the traditional approach to Process Validation?

Answer 40

- Process Validation, and stop after 3 consecutive successful production abtches - Then Revalidation, only if there were changes to critical processes, equipment and materials